Enantiospecific Synthesis of Aniline-Derived Sulfonimidamides

Reaction of sulfonimidoyl fluorides with anilines and Ca(NTf2)2 results in the formation of chiral sulfonimidamides. The reaction proceeds with inversion of the stereocenter at a sulfur atom. Enantiospecificity of the reaction was observed for all studied non-heterocyclic anilines. Combined experimental and computational mechanistic studies highlight chelate-type coordination of the sulfonimidoyl group to Ca(NTf2)2 and the formation of a SN2-like transition state, in which leaving F– coordinates with the Ca2+ ion.


General information and methods
All commercial chemicals were used as received and stored under argon. Racemic sulfonimidoyl fluoride 1 was synthesized according to the literature, 1 while chiral sulfonimidoyl fluoride 1 was synthesized according to the literature. 2 Reagents were used without further purification unless otherwise noted. Unless otherwise noted, all reactions were performed using glassware without further preparation. Certain reactions were carried out in anhydrous conditions. This utilized oven-dried glassware which was heated in an oven above 100 ℃ for at least 5 h or which was dried under vacuum with a heat gun (T > 200 ℃), under oxygen-free and water-free conditions. After weighing any solids, the glassware was connected to a Schlenk line, and then placed under vacuum and flushed with nitrogen gas (repeated 3 times). Liquids were added via syringe through a rubber septum. An oil bath was used as the heat source. Solvent abbreviations are: tetrahydrofuran (THF), ethyl acetate (EtOAc), dichloromethane (DCM), isopropyl alcohol (IPA), methanol (MeOH), tert-amyl alcohol (t-amylOH), petroleum ether 40-60 (P.E.). Solvents were used as received without any distillation with the exception of t-amylOH which was distilled over sodium before use. Flash column chromatography was performed using a Biotage® system, SiliCycle® precast silica columns (200−300 mesh or 300−400 mesh) and silica gel 40-63 µm. TLC analysis was performed on pre-coated, alumina-backed silica gel plates. TLC plates were analyzed by UV fluorescence (254 nm) or I 2 stain. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer at 298 K. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. The chemical shifts are listed in ppm on the δ = scale and coupling constants were recorded in Hertz (Hz). Chemical shifts are calibrated relative to the signals of corresponding non-deuterated solvents (CHCl 3 : δ = 7.26 ppm for 1 H and 77.16 ppm for 13 C, DMSO: δ = 2.50 ppm for 1 H and 39.52 ppm for 13 C). Abbreviations are used in the description of NMR data as follows: chemical shift (δ = ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet and m = multiplet), coupling constant (J, Hz). Highresolution mass spectra (HRMS) were measured on a QTOF micro spectrometer using electrospray ionization (ESI) in positive mode (ESI + ) or in negative mode (ESI -). Enantioselectivity was monitored using an HPLC Chiralpak IA column. A reference, racemic product was synthesized to determine the column conditions for baseline separation. Optimization of reaction conditions was monitored using Agilent 1290 Infinity UHPLC equipped with Zorbax SB C-18 HPLC column for analysis of reaction outcome. The column conditions for baseline separation were found to be H 2 O:MeCN, (50:50 v/v) + 0.1% formic acid, flow rate 0.6 mL/min, oven temperature 23 C, detector wavelength 238 nm.

Reactions with benzanilide
Benzanilide (49.3 mg; 0.25 mmol; 1.09 equiv) was charged into an oven dried 50 mL round bottom flask and flushed with N 2 . 10 mL of dry THF was added and the solution was cooled to -78 C. At this temperature, n-BuLi 2.5 M hexanes (0.16 mL; 0.26 mmol; 1.1 equiv) was added dropwise. After 30 min, sulfonimidoyl fluoride 1 (63.9 mg; 0.23 mmol; 1 equiv) was added to the reaction mixture in one portion. The reaction mixture was allowed to warm up to room temperature and the reaction was monitored by TLC at 1, 5 and 24 h. After 24 h, the reaction mixture was quenched with methanol. TLC and HRMS did not show the target product S1.
Benzanilide (49.3 mg; 0.25 mmol; 1.09 equiv) was charged into an oven dried 50 mL round bottom flask and flushed with N 2 . 10 mL of dry DMF was added and the solution was cooled to 0 C. At this temperature, sodium hydride 60% dispersion in mineral oil (13.19 mg; 0.33 mmol; 1.4 equiv) was added.
After 30 min, sulfonimidoyl fluoride 1 (63.9 mg; 0.23 mmol; 1 equiv) was added to the reaction mixture in one portion. The reaction mixture was allowed to warm up to room temperature and the reaction was monitored by TLC at 1, 5 and 24 h. After 32 h, the reaction mixture was heated to 60 C for 24 h. TLC and HRMS did not show the target product S1.

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Benzanilide (49.3 mg; 0.25 mmol; 1.09 equiv) was charged into an oven dried 50 mL round bottom flask and flushed with N 2 . 10 mL dry acetonitrile was added along with DBU (40 µL; 0.27 mmol; 1.2 equiv). After 30 min, sulfonimidoyl fluoride 1 (63.9 mg; 0.23 mmol; 1 equiv) was added to the reaction mixture in one portion. The reaction mixture was monitored by TLC at 1 and 2 h. After 2 h, the reaction mixture was heated to 60 C for 16 h. TLC and HRMS did not show the target product. S1 Benzanilide (49.3 mg; 0.25 mmol; 1.09 equiv) was charged into an oven dried 50 mL round bottom flask and flushed with N 2 . 10 mL of dry DMF was added along with K 2 CO 3 (40 mg, 0.25 mmol; 1.09 equiv). After 30 min, sulfonimidoyl fluoride 1 (63.9 mg; 0.23 mmol; 1 equiv) was added to the reaction mixture in one portion. The reaction mixture was monitored by TLC at 1 and 2 h. After 2 h, the reaction mixture was heated to 80 C for 16 h. TLC and HRMS did not show the target product S1.

Reactions with acetanilide
Acetanilide (34 mg; 0.25 mmol; 1.09 equiv) was charged into an oven dried 50 mL round bottom flask and flushed with N 2 . 10 mL dry THF was injected then the mixture was cooled to -78 C. At this temperature, n-BuLi (0.16 mL; 0.26 mmol; 1.1 equiv) was added dropwise. After 30 min, sulfonimidoyl fluoride 1 (63.9 mg; 0.23 mmol; 1 equiv) was added to the reaction mixture in one portion. The reaction mixture was allowed to warm up to room temperature and the reaction was monitored by TLC at 1, 5 and 24 h. After 120 h, the reaction mixture was quenched with methanol. TLC and HRMS did not show the target product S2. Acetanilide (34 mg; 0.25 mmol; 1.09 equiv) was charged into an oven dried 50 mL round bottom flask and flushed with N 2 . 10 mL dry THF was added and the solution was cooled to 0 C. At this temperature, sodium hydride 60% dispersion in mineral oil (13.19 mg; 0.33 mmol; 1.4 equiv) was added. After 30 min, sulfonimidoyl fluoride 1 (63.9 mg; 0.23 mmol; 1 equiv) was added to the reaction mixture in one portion. The reaction mixture was allowed to warm up to room temperature and the reaction was monitored by TLC at 1, 5 and 48 h. After 100 h, the reaction mixture was heated to 80 C for 24 h. TLC and HRMS did not show the target product S2. Sulfonimidoyl fluoride 1 (25 mg; 0.09 mmol; 1 equiv), aniline (24 µL; 0.09 mmol; 1 equiv), Lewis acid (0.09 mmol; 1 equiv) and base (0.09 mmol; 1 equiv) were charged into an 4 mL vial. 0.45 mL t-amylOH was injected and the reaction mixture was stirred for 5 h.

LC calibration for quantitative analysis
HPLC with a UV-Vis detector was used to determine the yields. Baseline separation was achieved within 5 min. using the conditions as described in general information and methods section. HPLC samples were prepared using 30 µL aliquotes (without work up) that were diluted with 1 mL of a 50:50 (v/v) mixture of water : acetonitrile. A typical HPLC chromatogram is shown in Figure S1. The peak at t r = 0.264 min corresponds to aniline, the peak at t r = 0.719 min corresponds to the hydrolysis product S3, the peak at t r = 2.167 min belongs to target product 2a and the peak at 3.152 min belong to starting material 1. A calibration was done using an external reference (1,3,5-tribromobenzene). The externally calibrated absorption coefficients are summarized in Table S1.   [a] Reaction was performed using THF as solvent and monitored by TLC (Hex (2)/EtOAc (1)); TLC showed only hydrolysis product was formed.  [a] Reaction was performed using 2 equiv. of Ca(NTf2)2 and was monitored by 19 F NMR using 4-fluoro-o-xylene as internal standard; conversion is reported in place of yield.

Discussion
Reaction optimization was performed using sulfonimidoyl fluoride 1 and aniline as starting materials and included variation of Lewis acids, bases, temperature, solvents and concentration. Because sulfonimidoyl fluorides can act as bidentate ligands, while sulfonyl fluorides are monodentate, we did not initially expect to arrive to reaction conditions similar to those reported by Ball. 3 Initially, we thought that sulfonimidoyl fluorides would be better activated with softer Lewis acids due to the presence of sulfonimine bond. 4 However, we found that hard Lewis acids such as Ca 2+ , Mg 2+ and Ba 2+ gave higher yield compared to softer acids Li + and Zn 2+ (Table 1). Furthermore, counter ion of the Lewis acid played an important role in this reaction as Ca(NTf 2 ) 2 gave higher conversion in comparison with Ca(OTf) 2 . Interestingly, the choice of base was important in order to prevent the side hydrolysis of 1 (Table S2). The use of two equivalents of aniline as both base and nucleophile resulted in virtually quantitative yield in t-amylOH without the formation of hydrolysis side-products. The reaction performs well in protic solvents (t-amylOH, t-BuOH, i-PrOH), but does not work in polar aprotic solvents such as DMF and DMSO. Furthermore, we discovered that a complete conversion of starting material can be reached with 1 equiv of Ca(NTf 2 ) 2 at 80 °C in 0.23 M solution within 5 h. The reaction with 2 equivs of Ca(NTf 2 ) 2 reached 95% conversion at room temperature within 5 h.
1.25 mL of tert-amyl alcohol was injected and the reaction mixture was heated to 80 C. After 5 or 24 h, the reaction mixture was cooled to room temperature and diluted with 10 mL ethyl acetate. This mixture was washed with 20 mL saturated NaCl, and the residue aqueous phase was extracted by ethyl acetate (2 x 10 mL). All the organic phases were combined and dried with Na 2 SO 4 . After the concentration of the organic solution, the residue mixture was further purified via flash column chromatography to give the target product.

General procedure B:
The sulfonimidoyl fluoride 1 (0.5 mmol, 139 mg, 1 equiv), aromatic amine (1.5 mmol, 3 equiv), and calcium triflimide (0.5 mmol, 300 mg, 1 equiv) were charged into an oven-dried 10 mL vial. 3 mL of tert-amyl alcohol was injected and the reaction mixture was heated to 80 ℃. After 2 h, the reaction mixture was cooled to room temperature and diluted with 20 mL ethyl acetate. This mixture was washed by 50 mL saturated NH 4 Cl, and the residue aqueous phase was extracted by ethyl acetate (2  20 mL).
All the organic phases were combined and dried with Na 2 SO 4 . After the concentration of the organic solution, the residue mixture was further purified via flash column chromatography to give the target product.

X-Ray crystallographic data of (S)-2b and (S)-2d
The selected crystal was mounted onto a goniometer head and cooled to 150K with an Oxford Cryosystem. Intensity data were collected on a SuperNova, Dual, Cu at zero, EosS2 using a Cu microfocus source (λ = 1.54184) Å.
Unit cell determination, data collection, data reduction and a symmetry-related (multi-scan) absorption correction were performed using the CrysAlisPro software. 5 The structure was solved with SHELXT and refined by a full-matrix least-squares procedure based on F 2 (Shelxl-2019/2). 6 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed onto calculated positions and refined using a riding model.
Additional programs used for analyzing data and their graphical manipulation included: SHELXle, 7 Mercury. 8

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Single crystals of (S)-2b were obtained by recrystallization from Hexane/EtOAc, and the absolute configuration was confirmed by X-ray crystallography. Figure S34. X-Ray crystallography structure of (S)-2b

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Single crystals of (S)-2d were obtained by recrystallization from Hexane/EtOAc, and the absolute configuration was confirmed by X-ray crystallography. Figure S35. X-Ray crystallography structure of (S)-2d

Computational studies
All DFT calculations were performed using the Gaussian 16 (version c01) package. 9 The ωB97XD functional 10 combined with the 6-311+G(d,p) basis set as implemented in there was used for geometry optimizations and vibrational frequency calculations. The transition states were confirmed by vibrational frequency analysis with only one imaginary vibration along the reaction coordinate and the reaction paths were followed using intrinsic reaction coordinate (IRC) calculations. Reaction energies reported in this study are Gibbs free energies at 353 K and ambient pressure, including solvation correction with the PCM solvent model.

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Coordinates of all DFT model compounds: